Clinical Trials with IL12

IL12 的临床试验

• 批准号: 6405901
• 负责人: JAMES W MIER
• 金额: $ 15.3万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-06-18 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6405901
• 关键词: DNA methylation; JAK kinase; T lymphocyte; clinical trials; enzyme activity; enzyme induction /repression; enzyme linked immunosorbent assay; flow cytometry; genetic promoter element; human subject; human therapy evaluation; interferon gamma; interleukin 12; leukocyte activation /transformation; melanoma; metastasis; monophenol monooxygenase; neoplasm /cancer immunology; neoplasm /cancer immunotherapy; oncoproteins; patient oriented research; phosphoproteins; polymerase chain reaction; renal cell carcinoma

Although prolonged IL-12 treatment has been shown to increase the number of peripheral blood CD8' T cells expressing memory phenotypic markers, the antigenic specificity of these cells has not been examined. One of the objectives of this application is to perform serial ELISPOT and tetramer analyses to determine if systemic IL-12 treatment affects the number or phenotype of circulating CD8+ T cells capable of recognizing defined melanoma peptide antigens in vitro. We have shown that the induction of IFNgamma, a critical determinant of IL-12-induced tumor regression, progressively declines with successive IL-12 injections and the extent of this down modulation correlates negatively with clinical outcome. Although this apparent desensitization to IL-12 is most likely an innate physiologic mechanism designed to restrict the duration and severity of TH 1 immune responses, it may also limit the therapeutic utility of IL-12 as an antitumor agent. The elucidation of the molecular mechanism underlying the failure to sustain IL-12-induced IFNgamma production is therefore a priority and one of the objectives of this application. Preliminary data suggest that this failure cannot be attributed to a disappearance of cells expressing IL-12 receptors or a global loss of STATs in PBL. The studies proposed in this application will evaluate events downstream of receptor engagement such as the ability of IL-12 and other cytokines to induce STAT phosphorylation in vitro in PBL obtained at various time points throughout the course of IL-12 treatment. The studies will also assess the effects of IL- 12 treatment on the expression of inhibitors of cytokine signaling (e.g. the Suppressor of Cytokine Signaling or SOCS family members) and on the regulable members of Janus Kinase (JAK) family. Finally, since the limited production of IFNgamma by TH2 and virus-infected T cells has been shown to be secondary to hypermethylation of the IFNgamma promoter, we propose to evaluate the state of methylation of this promoter in PBL obtained serially throughout the course of IL-12 treatment. Collectively, these studies may provide insights into the regulation of IL-12 responses and offer clues as to how the antitumor activity of this important cytokine might be enhanced.

尽管长期的IL-12治疗可以增加外周血中表达记忆表型标志的CD8‘T细胞的数量，但这些细胞的抗原性尚未得到检验。这项应用的目标之一是进行一系列ELISPOT和四聚体分析，以确定系统性IL-12治疗是否影响体外能够识别特定黑色素瘤多肽抗原的循环CD8+T细胞的数量或表型。我们已经证明，作为IL-12诱导肿瘤消退的关键决定因素，IFNGamma的诱导随着连续注射IL-12而逐渐下降，这种下调的程度与临床结果负相关。尽管这种对IL-12的明显脱敏很可能是一种天生的生理机制，旨在限制TH-1免疫反应的持续时间和严重程度，但它也可能限制IL-12作为抗肿瘤药物的治疗作用。因此，阐明IL-12诱导的干扰素产生失败的分子机制是这项应用的优先事项和目标之一。初步数据表明，这种失败不能归因于表达IL-12受体的细胞的消失或PBL中STATS的全球丢失。本申请中提出的研究将评估受体结合的下游事件，如IL-12和其他细胞因子在体外诱导PBL STAT磷酸化的能力，该能力在整个IL-12治疗过程中的不同时间点获得。这些研究还将评估IL-12治疗对细胞因子信号转导抑制物(例如，细胞因子信号转导抑制物或SOCS家族成员)和Janus Kinase(JAK)家族可调节成员表达的影响。最后，由于TH2和病毒感染的T细胞产生的有限的IFNGamma被证明是继发于IFNGamma启动子的高甲基化，我们建议评估在IL-12治疗过程中连续获得的PBL中该启动子的甲基化状态。总而言之，这些研究可能为IL-12反应的调节提供洞察力，并为如何增强这种重要细胞因子的抗肿瘤活性提供线索。